[Federal Register Volume 70, Number 225 (Wednesday, November 23, 2005)]
[Rules and Regulations]
[Pages 70720-70730]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-23120]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 312
[Docket No. 2000N-1663]
RIN 0910-AA61
Investigational New Drugs: Export Requirements for Unapproved New
Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations on the exportation of investigational new drugs, including
biological products. The final rule describes four different mechanisms
for exporting an investigational new drug product. These provisions
implement changes in FDA's export authority resulting from the FDA
Export Reform and Enhancement Act of 1996 and also simplify the
existing requirements for exports of investigational new drugs.
DATES: This rule is effective December 23, 2005.
FOR FURTHER INFORMATION CONTACT: Philip L. Chao, Office of Policy and
Planning (HF-23), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-0587.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of June 19, 2002 (67 FR 41642), we (FDA)
published a proposed rule to describe various options for exporting an
investigational new drug, including a biological product. We issued the
proposed rule to implement statutory changes resulting from the FDA
Export Reform and Enhancement Act of 1996 (Pub. L. 104-134, as amended
by Pub. L. 104-180) and to modify a pre-existing regulatory program for
exporting investigational new drugs.
Under current Sec. 312.110(b) (21 CFR 312.110(b)), any person who
intends to export an unapproved new drug product for use in a clinical
investigation must have either an investigational new drug application
(IND) or submit a written request to us (FDA). The written request must
provide sufficient information about the drug to satisfy us that the
drug is appropriate for investigational use in humans, that the drug
will be used for investigational purposes only, and that the drug may
be legally used by the consignee in the importing country for the
proposed investigational use (see Sec. 312.110(b)(2)(i)). The request
must also specify the quantity of the drug to be shipped and the
frequency of expected shipments (id.). If we authorize exportation of
the drug, we notify the government of the importing country (id.).
Similar procedures exist for export requests made by foreign
governments (see Sec. 312.110(b)(2)(ii)). Section 312.110(b)(3) states
that the requirements in paragraph (b) apply only where the drug is to
be used for the purpose of a clinical investigation. Section
312.110(b)(4) states that the requirements in paragraph (b) do not
apply to the exports of new drugs approved or authorized for export
under
[[Page 70721]]
section 802 of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 382) or section 351(h)(1)(A) of the Public Health Service Act.
The program for exporting investigational new drugs is commonly
known as the ``312 program'' because the regulation pertaining to the
program is located in part 312 (21 CFR part 312). Between fiscal years
1994 and 1997, we received nearly 1,800 export requests under the 312
program. We found that very few requests (less than 1 percent)
presented any public health concerns.
In 1996, the FDA Export Reform and Enhancement Act of 1996 became
law. The FDA Export Reform and Enhancement Act created, among other
things, two new provisions that affect the exportation of
investigational drug products, including biological products. One
provision, now section 802(b)(1)(A) of the act, authorizes exportation
of an unapproved new drug to any country if that drug has valid
marketing authorization by the appropriate authority in Australia,
Canada, Israel, Japan, New Zealand, Switzerland, South Africa, the
European Union (EU), or a country in the European Economic Area (EEA)
and certain other requirements are met. These countries are listed in
section 802(b)(1)(A)(i) and (b)(1)(A)(ii) of the act and are sometimes
referred to as the ``listed countries.'' Currently, the EU countries
are Austria, Belgium, Cyprus, the Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal,
Slovakia, Slovenia, Spain, Sweden, and the United Kingdom. The EEA
countries are the EU countries, and Iceland, Liechtenstein, and Norway.
The list of countries in section 802(b)(1)(A)(i) of the act will expand
automatically if any country accedes to the EU or becomes a member of
the EEA. Exports under section 802(b)(1)(A) of the act can encompass
exportation of an unapproved new drug product for investigational use
in a foreign country if the exported drug product has marketing
authorization in any listed country and the relevant statutory
requirements are met. Exports under section 802(b)(1)(A) of the act do
not require prior FDA authorization.
The second provision, now section 802(c) of the act, permits
exportation of unapproved new drugs intended for investigational use to
any listed country in accordance with the laws of that country. Exports
of drugs to the listed countries under section 802(c) of the act do not
require prior FDA authorization and are exempt from regulation under
section 505(i) of the act (21 U.S.C. 355(i)).
All drug products exported under section 802 of the act are,
however, subject to certain general requirements. Section 802(f) of the
act prohibits export if the unapproved new drug:
Is not manufactured, processed, packaged, and held in
substantial conformity with current good manufacturing practice (CGMP)
requirements;
Is adulterated under certain provisions of section 501 of
the act (21 U.S.C. 351);
Does not comply with section 801(e)(1) of the act (21
U.S.C. 381(e)(1)), which requires that the exported product be intended
for export, meet the foreign purchaser's specifications, not be in
conflict with the laws in the importing country, be labeled on the
outside of the shipping package that the products are intended for
export, and not be sold or offered for sale in the United States;
Is the subject of a determination by FDA that the
probability of reimportation of the exported drug would present an
imminent hazard to the public health and safety of the United States;
Presents an imminent hazard to the public health of the
foreign country;
Fails to comply with labeling requirements in the country
receiving the exported drug; or
Is not promoted in accordance with labeling requirements
in the importing country and, where applicable, in the listed country
in which the drug has valid marketing authorization.
Section 802(g) of the act also imposes certain recordkeeping and
notification obligations on drugs exported under section 802 of the
act. In the Federal Register of December 19, 2001 (66 FR 65429), we
issued a final rule on these recordkeeping and notification
requirements, and the rule is codified at Sec. 1.101 (21 CFR 1.101).
The new export provisions in section 802 of the act significantly
reduced the number of requests under the 312 program from an annual
average of 570 requests to 200 requests. This final rule amends Sec.
312.110 to conform to the FDA Export Reform and Enhancement Act of 1996
and to modify the 312 program.
II. Comments on the Proposed Rule
A. What Did the Proposed Rule Cover? How Many Comments Did FDA Receive?
The proposed rule would amend Sec. 312.110 to provide four
mechanisms for exporting investigational new drugs, eliminate
unnecessary language in the current regulation, and modify the export
requirements for the 312 program. The proposed rule would not contain
any new recordkeeping requirements because such records are already
required under Sec. 312.57 (if the foreign clinical trial is under an
IND) or Sec. 1.101.
We received eight comments on the proposed rule. The comments came
from seven sources: A pharmaceutical trade association, four
pharmaceutical companies, one consulting firm, and one university
student. In general, six comments strongly supported the rule with few
or no modifications. One comment opposed exports of investigational new
drugs generally, and another comment sought clarification of one
statutory provision and did not address the rule itself. We address
most comments in greater detail below. (We do not discuss the comment
seeking a clarification of the statute because it was not directly
related to the rule.) To make it easier to identify comments and our
responses, the word ``Comment,'' in parenthesis, will appear before the
comment's description, and the word ``Response,'' in parenthesis, will
appear before our response. We have also numbered each comment to
identify them more easily. The number assigned to each comment is
purely for organizational purposes and does not signify the comment's
value or importance or the order in which it was received.
B. Can Investigational New Drugs Be Exported Under an IND?
Proposed Sec. 312.110(b)(1) would represent the first mechanism
for exporting an investigational new drug and would apply if the
foreign clinical investigation is to be done under an IND. Proposed
Sec. 312.110(b)(1) would provide that an investigational new drug may
be exported from the United States if an IND is in effect for the drug
under Sec. 312.40, the drug complies with the laws of the country to
which it is being exported, and each person who receives the drug is an
investigator who will use the drug in a study submitted to and allowed
to proceed under the IND. Because this provision is not limited to
particular countries, a drug that is the subject of an IND could be
exported under the act to any country in the world if the export is for
the purpose of conducting a clinical investigation in the importing
foreign country. Exporters should be aware, however, that this
provision, like all provisions in proposed Sec. 312.110, pertain only
to the requirements of the act. Other Federal laws, such as those
relating to customs or controlled substances or barring
[[Page 70722]]
exports to specific countries, may restrict or prohibit an export even
if it would be permitted under this rule.
We received no comments on this provision and have finalized it
without change.
C. Can Investigational New Drugs Be Exported If They Have Marketing
Authorization? Which Countries Must Provide That Marketing
Authorization?
Proposed Sec. 312.110(b)(2) would represent the second mechanism
for investigational new drug exports and would implement section
802(b)(1) of the act with respect to exports of unapproved new drugs
for investigational use (although section 802(b)(1) of the act has been
in effect since April 1996). Under the proposal, if a drug product that
is not approved for use in the United States has valid marketing
authorization in Australia, Canada, Israel, Japan, New Zealand,
Switzerland, South Africa, or in any country in the EU or the EEA, the
drug may be exported for any use, including investigational use, to any
country, provided that the export complies with all applicable
requirements pertaining to exports. Prior FDA approval to export the
drug would not be required, nor would proposed Sec. 312.110(b)(2)
require the drug to be the subject of an IND. The exporter and the
exported products, however, would have to comply with the foreign
country's laws and with requirements in section 802(f) and (g) of the
act. The proposal would also require compliance with the export
notification and recordkeeping requirements Sec. 1.101.
We received no comments on this provision and have finalized it
without change.
However, regarding the export notification and recordkeeping
requirements at Sec. 1.101, we note that we received a petition for
reconsideration that challenges, among other things, the recordkeeping
requirement at Sec. 1.101(b)(2). Section 1.101(b)(2) describes the
records that may be kept to show that an export does not conflict with
a foreign country's laws, as required by section 801(e)(1)(B) of the
act. Section 1.101(b)(2) states that the records may consist of a
letter from an appropriate foreign government agency stating that the
product has marketing approval from the foreign government or does not
conflict with the foreign country's laws or a notarized certification
by a responsible company official in the United States that the product
does not conflict with the foreign country's laws. In a letter dated
July 22, 2002, we informed the petitioner that we would exercise
enforcement discretion regarding the letter and certification described
in Sec. 1.101(b)(2), that parties must still comply with the statutory
requirement in section 801(e)(1)(B) of the act, and that we would be
evaluating whether to issue an advance notice of proposed rulemaking
regarding the petitioner's issues (see Letter from Margaret M. Dotzel,
Associate Commissioner for Policy, to Peter Barton Hutt, Covington &
Burling, dated July 22, 2002; this letter can be found in FDA Docket
No. 1998N-0583). We subsequently issued an advance notice of proposed
rulemaking regarding the issues raised by the petitioner (see 69 FR
30842, June 1, 2004) and are continuing to evaluate the comments. We
are continuing to exercise enforcement discretion regarding Sec.
1.101(b)(2), but we remind would-be exporters that they must continue
to comply with the statutory requirement in section 801(e)(1)(B) of the
act and the remaining provisions in Sec. 1.101.
D. Can Investigational New Drugs Be Exported Directly to Certain
Countries Without FDA Approval?
Proposed Sec. 312.110(b)(3), the third mechanism for
investigational new drug exports, would implement section 802(c) of the
act with respect to exports of unapproved new drugs for investigational
use (although section 802(c) of the act has been in effect since April
1996). In brief, under proposed Sec. 312.110(b)(3), if an unapproved
drug is to be exported for investigational use to any listed country in
accordance with the laws of that country, then no prior FDA
authorization would be required. Exports of a drug for investigational
use under proposed Sec. 312.110(b)(3) would have to comply with the
foreign country's laws and the applicable statutory requirements in
section 802(c), (f), and (g) of the act. Proposed Sec. 312.110(b)(3)
would also require compliance with the relevant recordkeeping
requirements at Sec. 1.101.
Proposed Sec. 312.110(b)(3) would add that investigational new
drugs that are not under an IND and are exported under section 802(c)
of the act do not have to bear a label stating, ``Caution: New Drug-
Limited by Federal (or United States) law to investigational use.''
This proposed requirement reflected the fact that the label statement
is required under section 505(i) of the act, and that, absent an IND,
drugs exported under section 802(c) of the act are not subject to
section 505(i) of the act.
The preamble to the proposed rule discussed our interpretation of
section 802(c) of the act and the issue of ``transshipment.''
``Transshipment'' refers to the practice of shipping a product to a
country from which it will later be shipped to another country. We
stated that we were aware that some firms have interpreted section
802(c) of the act as permitting transshipment to unlisted countries as
long as the shipment went through a listed country (see 67 FR 41642 at
41643). (We knew about the firms' position on transshipment from
comments we had received on a draft export guidance document that
appeared in the Federal Register of June 12, 1998 (63 FR 32219).) We
noted that section 802(c) of the act is silent with respect to
transshipment, and a more reasonable interpretation is that the
provision does not allow transshipments. We added that interpreting
section 802(c) of the act to allow transshipment would be inconsistent
with our traditional practice under Sec. 312.110 and would presume, in
the absence of any supporting language in the statute or its
legislative history, that the listed countries may serve as mere
transfer points or conduits for investigational new drugs and devices
destined for unlisted countries (67 FR 41642 at 41643).
Nevertheless, because we knew that some firms insisted that section
802(c) of the act allows transshipment, the preamble to the proposed
rule stated that we would interpret section 802(c) of the act as
permitting investigational new drugs to be sent to principal
investigators in a listed country who then use the investigational new
drug in an unlisted country, provided that the principal investigator
conducts the clinical investigations in accordance with the
requirements of both the listed country and the unlisted country where
the investigation is conducted. For example, if firm A exported an
investigational new drug to principal investigator X in Norway (a
listed country), we stated that we would interpret section 802(c) of
the act as permitting exportation of the investigational new drug,
without prior FDA authorization, as long as firm A and the exported
drug met all other statutory conditions pertaining to the exportation.
Principal investigator X could then administer the investigational new
drug in an unlisted country so long as principal investigator X
conducted the clinical investigation in accordance with Norwegian
requirements and any requirements in the unlisted country where the
investigational new drug is administered.
(Comment 1) Three comments disagreed with this limited
transshipment position. The comments acknowledged that the law is
subject to
[[Page 70723]]
various interpretations, but argued against allowing transshipment from
listed countries to unlisted countries. The comments explained that a
clinical investigator may have little ability to control how a drug is
moved, stored, or used ``if he or she is not supported by the laws of
the land'' and so expecting the clinical investigator ``to enforce the
laws, regulations and practices of the listed country in the unlisted
country (even assuming there are no contradictions between them) is, we
believe, quite unrealistic and exposes the investigator, the sponsor
and, not least, the patients to significant risks.'' Consequently, two
comments recommended that we not allow transshipment from listed
countries to unlisted countries. Another comment stated that we should
not allow transshipment from listed countries to unlisted countries,
but then stated that transshipment of investigational new drugs should
be ``the responsibility of the sponsor alone.''
(Response) We have reconsidered our interpretation of section
802(c) of the act and agree that transshipment should not be permitted
under section 802(c) of the act. Although our limited transshipment
policy was intended to accommodate the industry, we agree with the
pharmaceutical industry comments that a clinical investigator's ability
to apply a listed country's laws and regulations in an unlisted country
may be difficult at best. Therefore, we do not interpret section 802(c)
of the act or Sec. 312.110(b)(3) as allowing transshipment from listed
countries to unlisted countries.
Furthermore, we do not agree that transshipment should be the
sponsor's responsibility alone because that would mean that a sponsor
could consider itself free to transship an investigational new drug
regardless of our interpretation of section 802(c) of the act.
As for proposed Sec. 312.110(b)(3) itself, we received no comments
on the provision and have finalized it without change.
E. What Changes Are Being Made to the ``312 Program?''
Proposed Sec. 312.110(b)(4) would represent the fourth mechanism
for exporting an investigational new drug and would pertain to
unapproved new drugs exported to any country for investigational use
without an IND, and we expected that the provision would be used by
persons who intend to export a drug that does not have valid marketing
authorization from a listed country for investigational use to an
unlisted country. Proposed Sec. 312.110(b)(4) would modify the 312
program by eliminating the requirement of prior FDA authorization. The
proposal would require a person seeking to export an unapproved new
drug for investigational use without an IND to send a written
certification to us. The certification would be submitted at the time
the drug is first exported and would describe the drug being exported
(i.e., trade name (if any), generic name, and dosage form), identify
the country or countries to which it is being exported, and affirm that
various conditions or criteria had been met, such as:
The drug is intended for export;
The drug is intended for investigational use in a foreign
country;
The drug meets the foreign purchaser's or consignee's
specifications;
The drug is not in conflict with the importing country's
laws;
The outer shipping package is labeled to show that the
package is intended for export from the United States;
The drug is not sold or offered for sale in the United
States;
The clinical investigation will be conducted in accordance
with Sec. 312.120;
The drug is manufactured, processed, packaged, and held in
substantial conformity with CGMPs;
The drug is not adulterated within the meaning of section
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;
The drug does not present an imminent hazard to public
health, either in the United States if the drug were to be reimported
or in the foreign country;
The drug is labeled in accordance with the foreign
country's laws; and
The drug is promoted in accordance with its labeling.
The preamble to the proposed rule explained that we were proposing
to accept certifications because our experience with the 312 program
indicated that very few investigational new drug exports under the
existing program raise any public health concerns. The certification
would eliminate the requirement of prior FDA authorization of a request
to export a drug for investigational use (67 FR 41642 at 41644).
Additionally, by conditioning exports to unlisted countries under the
312 program on the conduct of clinical investigations in accordance
with Sec. 312.120, the use of investigational new drugs under the 312
program would be subject to internationally recognized requirements for
clinical investigations (id. at 41645). The proposal would also require
the exporter of the investigational new drug to retain records showing
its compliance with the provision's requirements.
(Comment 2) Several comments expressed strong support for
streamlining the 312 program. For example, one comment called the
proposal a ``bold but considered move'' that would reduce
administrative burdens on FDA and sponsors without waiving any
significant obligations.
Three comments questioned why proposed Sec. 312.110(b)(4)(xii)
would require the exporter to certify that the investigational new drug
``is promoted in accordance with its labeling.'' The comments said that
the requirement is unnecessary because investigational new drugs are
not the subject of promotion and requested that we clarify or delete
the requirement.
(Response) We agree with the comments that investigational new
drugs are not to be promoted, and we have deleted the language
regarding promotion from Sec. 312.110(b)(4).
However, one comment's claim that proposed Sec. 312.110(b)(4)
would reduce administrative burdens without waiving any significant
obligations prompted us to consider whether a person exporting a drug
under Sec. 312.110(b)(4) should be able to export an investigational
new drug in an emergency without satisfying certain criteria. For
example, in recent years, we have seen growing concern over the
possible use of biological, chemical, or other weapons in a terrorist
attack. These concerns have prompted interest by some foreign countries
in stockpiling drugs and biological products for possible use if such
an attack occurs. We have also seen the sudden emergence of new
diseases, such as Severe Acute Respiratory Syndrome (SARS), and can
foresee situations where a foreign country might seek importation of an
investigational new drug to respond to a sudden and immediate disease
outbreak. In such situations, the need to stockpile drugs or to provide
potentially helpful treatment quickly to a large number of patients may
be incompatible with certain criteria in Sec. 312.110(b)(4).
Therefore, the final rule includes a new Sec. 312.110(b)(5) to
address the exportation of investigational new drugs due to a national
emergency in a foreign country. New Sec. 312.110(b)(5) contemplates
two different national emergency scenarios. The first scenario, at
Sec. 312.110(b)(5)(i), provides for exportation of an investigational
new drug in a foreign country to be stored for possible use if and when
a national emergency in that foreign country arises. Under Sec.
312.110(b)(5)(i), a person may export the investigational new drug
under Sec. 312.110(b)(4) and may exclude
[[Page 70724]]
from its certification an affirmation with respect to any one or more
of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi), (b)(4)(vii),
(b)(4)(viii), and/or (b)(4)(ix), provided that he or she:
Provides a written statement, under Sec.
312.110(b)(5)(i)(A)(1), explaining why compliance with each such
paragraph is not feasible or is contrary to the best interests of the
individuals who may receive the investigational new drug;
Provides a written statement from an authorized official
of the importing country's government. The statement must attest that
the official agrees with the exporter's statement made under Sec.
312.110(b)(5)(i)(A)(1); explain that the drug is to be stockpiled
solely for use of the importing country in a national emergency; and
describe the potential national emergency that warrants exportation of
the investigational new drug under this provision; and
Provides a written statement showing that the Secretary of
Health and Human Services (the Secretary), or his or her designee,
agrees with the findings of the authorized official of the importing
country's government.
We decided that in a national emergency, ``stockpiling'' scenario,
exporters should be able to drop the affirmations in paragraphs
(b)(4)(i), (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), and/or
(b)(4)(ix) from their certifications if, due to the potential national
emergency for which the drug is being stockpiled, compliance with that
paragraph is infeasible or contrary to the best interests of the
individuals who may receive the investigational new drug. For example,
several foreign governments have asked for our help in exporting
investigational vaccines to their countries to reduce their citizens'
vulnerability to a certain pathogen. Vaccine production is very
complex, so it is unlikely that a manufacturer could respond quickly to
a large-scale national emergency in a foreign country. Thus, if we were
to insist that all investigational vaccines exported in a national
emergency scenario be ``intended for export'' (as otherwise required by
Sec. 312.110(b)(4)(i)), vaccines that had been intended for domestic
use could not be exported to address a national emergency in a foreign
country because those vaccines would not have been ``intended for
export'' when they were first made. Providing for the deletion of the
``intended for export'' requirement in a national emergency,
stockpiling scenario makes it possible to export products originally
intended for domestic use to meet a more important foreign need.
In the national emergency, ``stockpiling'' scenario, exportation
may not proceed without prior FDA authorization. We decided to require
FDA authorization to ensure that exportation of a drug based on this
scenario is limited to the requirements set out in Sec.
312.110(b)(5)(i) and not used for other situations for which other
regulatory requirements apply.
The second national emergency scenario is at Sec.
312.110(b)(5)(ii). This provision would apply where the national
emergency is both sudden and immediate. For example, Sec.
312.110(b)(5)(ii) could be used when a bioterrorist attack has occurred
in a foreign country and has created an immediate need to export an
investigational new drug for use in the foreign country. It could also
apply where the national emergency is imminent, but has not yet
occurred. For example, Sec. 312.110(b)(5)(ii) might be applicable
where a foreign government has evidence showing that a particular novel
disease outbreak is about to occur and that prompt administration of an
investigational new drug is needed to treat or immunize its citizens
before the disease assumes epidemic proportions. Thus, in these
examples, the words ``sudden'' and ``immediate'' are meant to convey a
sense that the national emergency resulted from unforeseen
circumstances and that the exported drug is needed quickly in order to
address the national emergency, and we expect Sec. 312.110(b)(5)(ii)
to be used in very rare circumstances. In other words, Sec.
312.110(b)(5)(ii) should not be used in situations where a person
simply wants to export a drug to address longstanding public health
concerns (such as a disease which is and has been prevalent in the
foreign country for years).
Under Sec. 312.110(b)(5)(ii), a person may export an
investigational new drug under Sec. 312.110(b)(4) and exclude from its
certification an affirmation with respect to any one or more of
paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), (b)(4)(vi), (b)(4)(vii),
(b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that he or she:
Provides a written statement, under Sec.
312.110(b)(5)(ii)(A)(1), explaining why compliance with each such
paragraph is not feasible or is contrary to the best interests of the
individuals who are expected to receive the investigational new drug;
and
Provides sufficient information from an authorized
official of the importing country's government to enable the Secretary,
or his or her designee, to decide whether a national emergency has
developed or is developing in the importing country, whether the
investigational new drug will be used solely for that national
emergency, and whether prompt exportation of the investigational new
drug is necessary.
We decided that, in the case of a sudden and immediate national
emergency in a foreign country, the exporter's certification may omit
an affirmation addressing paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v),
(b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix) and/or (b)(4)(xi) if,
due to the sudden and immediate national emergency, compliance with
that paragraph or paragraphs are infeasible or contrary to the best
interests of the individuals who may receive the investigational new
drug. For example, it would not be necessary to insist that the
exported drug be labeled in accordance with the foreign country's laws
where the foreign country itself had agreed that compliance with its
labeling requirements was unnecessary during the national emergency.
Additionally, in contrast to the ``stockpiling'' scenario in Sec.
312.110(b)(5)(i), exportation to meet a sudden and immediate national
emergency may not proceed until the Secretary has decided whether a
national emergency has developed or is developing in the importing
country, whether the investigational new drug will be used solely for
that national emergency, and whether prompt exportation of the
investigational new drug is necessary. We reiterate that, given its
reference to a ``sudden and immediate'' national emergency, Sec.
312.110(b)(5)(ii) should be very rarely used.
Persons who wish to obtain a written statement from the Secretary
under Sec. 312.110(b)(5)(i) or to request that the Secretary make the
determinations under Sec. 312.110(b)(5)(ii) should direct their
requests to: Secretary's Operations Center, Office of Emergency
Operations and Security Programs, Office of Public Health Emergency
Preparedness, Office of the Secretary, Department of Health and Human
Services, 200 Independence Ave. SW., Washington, DC 20201.
Requests may be also be sent by FAX: 202-619-7870 or by e-mail:
[email protected].
To complement these changes, we have revised Sec. 312.110(c)(4) to
state that exportation is not allowed under Sec. 312.110(b)(4) if the
conditions underlying the certification or the statements submitted
under Sec. 312.110(b)(5) are no longer met.
(Comment 3) One comment appeared to inquire whether transshipment
could occur under the 312 program. The comment suggested that
transshipment should be allowed if the sponsor amended its
``certification'' requesting shipment of an investigational new drug
[[Page 70725]]
from either a listed or unlisted country to another unlisted country
``where the protocol is unchanged and all applicable laws are met.''
The comment added that only products under the sponsor's direct control
would be permitted for transshipment.
(Response) The comment may have misinterpreted the rule. Exports of
an investigational new drug to a listed country fall within section
802(c) of the act and Sec. 312.110(b)(3), and no certification is
required. Consequently, if an investigational new drug is exported to a
listed country under section 802(c) of the act, there is no
``certification'' to amend, and, as our response to comment 1 of this
document stated, we will not interpret section 802(c) of the act as
allowing transshipment from a listed country to an unlisted country.
As for exports under the 312 program and Sec. 312.110(b)(4), we
concede that our proposed revision of the 312 program did not prohibit
its use for exports to listed countries. However, if a sponsor decided
to use Sec. 312.110(b)(4) to export an investigational new drug to a
listed country, it would create unnecessary work for itself because,
under Sec. 312.110(b)(3), it could export the investigational new drug
to the listed country without providing any documentation to us.
If the comment sought to use Sec. 312.110(b)(4) to export an
investigational new drug to an unlisted country and then transship that
drug to another unlisted country, we would agree that Sec.
312.110(b)(4) could be used, but only if both unlisted countries are
identified in the original certification to us. In other words, the
original certification would have to state that the investigational new
drug is being sent to one unlisted country and then shipped to another
unlisted country. We do not intend to permit sponsors to use Sec.
312.110(b)(4) to ship investigational new drugs to an unlisted country
and, at some later, unspecified date, amend the certification in the
manner described by the comment. We are concerned that allowing
amendments to certifications that would change the country receiving
the exported drug would enable an unscrupulous person to avoid several
critical obligations, particularly those that are specific to the
receiving country, such as ensuring that:
The clinical investigation will be conducted in accordance
with Sec. 312.120;
The drug meets the foreign purchaser's or consignee's
specifications; and
The drug does not present an imminent hazard to the public
health in the foreign country.
Given these concerns, we decline to revise the rule to allow
amended certifications under Sec. 312.110(b)(4) that would enable
sponsors to transship investigational new drugs without observing
several important obligations in Sec. 312.110(b)(4) itself.
F. Are There Any Restrictions on Investigational New Drug Exports?
Proposed Sec. 312.110(c) would prohibit exports under certain
conditions. For example, for drugs under an IND that are exported under
proposed 312.110(b)(1), exportation would not be allowed if the IND is
no longer in effect. For drugs exported under proposed Sec.
312.110(b)(2), (b)(3), or (b)(4), exportation would not be allowed if
the requisite conditions underlying or authorizing the exportation are
no longer met. For all investigational new drugs exported under
proposed Sec. 312.110, exportation would not be allowed if the drug no
longer complied with the laws of the importing country.
We received no comments on this provision. However, as explained in
section II.E of this document, we have created a Sec. 312.110(b)(5) to
address exportation of investigational new drugs to meet national
emergencies in a foreign country. This new provision establishes new
conditions on the export requirements under Sec. 312.110(b)(4) in such
national emergencies. Consequently, we have revised Sec. 312.110(c)(4)
to state that exportation is not allowed under Sec. 312.110(b)(4) if
the conditions underlying the certification or the statements submitted
under Sec. 312.110(b)(5) are no longer met.
G. What Other Changes Did FDA Propose?
The proposed rule would also make several minor amendments to
reflect or update statutory requirements and to redesignate paragraphs
(to accommodate other proposed changes). In brief, the proposal would:
Redesignate Sec. 312.110(b)(4) as new Sec. 312.110(d) to
state that the export requirements in Sec. 312.110 do not apply to
insulin or to antibiotic drug products exported for investigational
use. This provision would reflect section 802(i) of the act which
provides that insulin and antibiotics may be exported in accordance
with the export requirements in section 801(e)(1) of the act without
complying with section 802 of the act.
Eliminate a potentially confusing and incorrect reference
to new drugs ``* * *approved or authorized for export under section 802
of the act * * * or section 351(h)(1)(A) of the Public Health Service
Act'' because the FDA Export Reform and Enhancement Act eliminated most
FDA approval requirements for exported drugs. As for section 351(h) of
the Public Health Service Act, it pertains to exports of partially
processed biological products that are: (1) Not in a form applicable to
the prevention, treatment, or cure of diseases or injuries of man; (2)
not intended for sale in the United States; and (3) intended for
further manufacture into final dosage form outside the United States.
Thus, partially processed biological products exported under section
351(h) of the Public Health Service Act are not exported for
investigational use, so they do not have to be mentioned in Sec.
312.110. We also noted that the FDA Export Reform and Enhancement Act
of 1996 revised and renumbered section 351(h) of the Public Health
Service Act, and so the revised section no longer contains a paragraph
(h)(1)(A) (see 67 FR 41642 at 41645).
Amend the authority citation for part 312 to reflect
additional statutory provisions, such as sections 801, 802, 803, and
903 of the act (21 U.S.C. 381, 382, 383, and 393), that affect
investigational new drug exports, FDA's international activities, and
rulemaking.
Remove the text at Sec. 312.110(b)(3) stating that the
export requirements in Sec. 312.110(b) apply only where the drug is to
be used for the purpose of a clinical investigation. We proposed to
delete this language because the proposed rule expressly refers to
exports of investigational new drugs for use in clinical
investigations.
We received no comments on these provisions or changes and have
finalized them without change.
H. What Other Comments Did FDA Receive?
Several comments responded to specific questions we had presented
in the preamble to the proposed rule or discussed other issues related
to the export of investigational new drugs or the conduct of foreign
clinical trials.
The preamble to the proposed rule noted that section 402(j) of the
Public Health Service Act (42 U.S.C. 282(j)) directs the Secretary to
establish, maintain, and operate a data bank of information on clinical
trials for drugs for serious or life-threatening diseases and
conditions (67 FR 41642 at 41645). We invited comment on whether we
should make available information on clinical trials involving
investigational new drugs exported under proposed Sec. 312.110(b)(4).
[[Page 70726]]
(Comment 4) Some comments opposed making information on drugs
exported under proposed Sec. 312.110(b)(4) publicly available. The
comments argued that section 402(j) of the Public Health Service Act
was intended to provide clinical trial information to American patients
and that we had no legal authority to collect or disclose information
on foreign clinical trials.
(Response) We agree with the comments that section 402(j) of the
Public Health Service Act does not apply to exports under Sec.
312.110(b)(4), but disagree as to the rationale. Section 402(j) of the
Public Health Service Act refers to ``clinical trials'' without any
express requirement that the clinical trials be conducted in the United
States. However, we believe that this provision only applies to
clinical trials conducted under an IND.
The Senate Committee on Labor and Human Resources' report on the
``Food and Drug Administration Modernization and Accountability Act of
1997'' describes the data bank as requiring sponsors of clinical trials
to provide certain clinical trial information to the National
Institutes of Health ``not later than 21 days after the approval by the
FDA'' (see S. Rept. 105-43, ``Food and Drug Administration
Modernization and Accountability Act of 1997,'' 105th Cong., 1st sess.
at p. 99 (July 1, 1997)). The report apparently meant not later than 21
days after the IND goes into effect since, strictly speaking, FDA does
not ``approve'' clinical trials or INDs. Rather, an IND goes into
effect after 30 days if FDA does not notify the sponsor that the trials
are subject to a clinical hold before then, or earlier than 30 days if
FDA so notifies the sponsor that the trials may begin. Nonetheless,
this statement strongly suggests that only trials that are conducted
under an IND are to be included in the data bank. Therefore, based on
this legislative history, we do not interpret section 402(j) of the
Public Health Service Act as applying to exports under Sec.
312.110(b)(4).
(Comment 5) One comment focused on the proposed rule's cross-
references to statutory provisions. The comment said that the cross-
references ``greatly complicate the reading and practical understanding
of the regulation'' and suggested that we incorporate the statutory
language directly into the rule.
(Response) We decline to amend the rule as suggested by the
comment. While we understand that cross-references in a regulation can
make it more difficult to read and to understand a particular
requirement, there are several practical reasons for not inserting
statutory language into a rule. First, several of the cited statutory
provisions contain cross-references themselves. Section 802(f) of the
act, which is mentioned in Sec. 312.110(b)(2), (b)(3), (c)(2), and
(c)(3), refers to certain adulteration provisions in section 501 of the
act and to export requirements at section 801(e)(1) of the act. Thus,
inserting statutory language into the rule would still result in cross-
references to other statutory provisions. Second, if we were to use
statutory language in the rule and if Congress amended that particular
statute later, we would be obliged to begin new rulemaking to reflect
the new statutory language, even if the revised statutory language had
no significant impact on the rule itself. Otherwise, the regulation
would be inconsistent with the act, and differences between the act and
the regulatory language could result in needless disagreements or
disputes. Third, inserting statutory language into a rule would make
the rule much longer and have limited value because a firm should be
conscious of both statutory and regulatory requirements. In general, we
may issue a regulation to describe our interpretation of a particular
statutory requirement and to create a consistent, enforceable
obligation on affected parties and on the agency itself. If a
particular statutory provision is self-executing or self-explanatory,
we may feel that no regulation is necessary. Given these
considerations, we decline to insert the statutory language into the
rule.
(Comment 6) One comment opposed the rule entirely. The comment
questioned why a foreign country would accept a drug that could not be
used in the United States and alleged that companies exported
investigational new drugs to avoid breaking U.S. law and to ``exploit
people in other countries.'' The comment suggested that companies
supporting the proposed rule ``should be investigated for unethical
conduct.''
(Response) We disagree with the comment. The mechanisms for
exporting an investigational new drug reflect statutory provisions in
sections 505(i), 802(b)(1), and 802(c) of the act. As a result,
contrary to the comment's assertion, firms exporting a drug for
investigational use in a foreign country in accordance with this rule
would be acting in compliance with the act. Given that fact, we have no
basis for attributing an improper or unethical motive to those who
would export such products or those who support this rulemaking.
(Comment 7) Several comments, in discussing their position against
transshipment, recommended that we ``work diligently to approve
unlisted countries and add them to the listed countries.''
(Response) We interpret the comments' suggestion of ``adding''
countries as referring to section 802(b)(1)(B) of the act, which states
that the Secretary ``may designate an additional country to be included
in the list of countries described in [section 802(b)(1)(A) of the
act]'' if certain requirements are met. However, section 802(b)(1)(B)
of the act also states that the authority to add countries to the list
cannot be delegated. As a result, FDA has no authority or ability to
add countries to the list.
We note that, since the FDA Export Reform and Enhancement Act
became law in 1996, we have not received any substantive inquiries
about adding a particular country to the group of listed countries. We
are not aware of any similar inquiries to the Department of Health and
Human Services.
III. Description of the Final Rule
The final rule is substantially similar to the proposed rule as it
describes four mechanisms for exporting a drug, including a biological
product, for investigational use. The four mechanisms are: (1)
Exporting an investigational new drug under an IND, where the foreign
clinical trial is covered in the IND; (2) exporting an investigational
new drug that has valid marketing authorization from a ``listed
country'' identified in section 802(b)(1)(A) of the act; (3) exporting
an investigational new drug to a listed country; or (4) providing a
certification to FDA and exporting the investigational new drug under a
modified ``312 program.'' In the latter case, the final rule also
identifies the certification criteria that must be followed if the
export is to occur under the 312 program.
To recap the principal features of each export mechanism,
1. Section 312.110(b)(1) could be used where the foreign clinical
trial is the subject of an IND.
2. Section 312.110(b)(2) could be used where the investigational
new drug has received market authorization in any ``listed country''
and complies with the laws of the country to which it is being
exported.
3. Section 312.110(b)(3) could be used when the investigational new
drug is to be used in a clinical investigation in a ``listed country.''
4. Section 312.110(b)(4) could be used in situations not covered by
Sec. 312.110(b)(1), (b)(2), or (b)(3), and the requirements in Sec.
312.110(b)(4) may be streamlined or modified in the event of
[[Page 70727]]
a national emergency in a foreign country (see Sec. 312.110(b)(5)).
Please note that the export mechanisms are not mutually exclusive.
For example, if a sponsor obtains an IND for a clinical investigation
in a listed country, the sponsor is not obliged to export the
investigational new drug under Sec. 312.110(b)(2) or (b)(3).
The final rule also describes the conditions under which
exportation may not occur. In general, these conditions are: (1) When
the export no longer complies with the statutory requirements that
would allow the drug to be exported; (2) when the conditions underlying
the certification in the 312 program are no longer met; or (3) when the
exported investigational new drug no longer complies with the foreign
country's laws.
The final rule also states that insulin and antibiotics may be
exported for investigational use in accordance with section 801(e)(1)
of the act. The act specifically states that exports of insulin and
antibiotics that are not approved for use by FDA are subject only to
section 801(e)(1) of the act.
IV. Legal Authority
Section 505(i) of the act authorizes the agency to issue
regulations pertaining to drugs intended solely for investigational use
by experts qualified by scientific training and experience to
investigate the safety and effectiveness of drugs. Under this
authority, FDA has, for many years, approved the export of certain
unapproved new drugs for investigational use in one or more foreign
countries. Additionally, FDA can, under its general authority over
investigational new drugs, terminate an IND under certain conditions.
The final rule is consistent with section 505(i) of the act insofar
as Sec. 312.110(b)(1) pertains to drugs that are the subject of an IND
and Sec. 312.110(b)(4) requires clinical investigations involving an
investigational new drug without an IND that is exported to a foreign
country to be conducted in accordance with Sec. 312.120. Section
505(i) of the act also gives FDA express authority to issue regulations
pertaining to investigational new drugs.
The final rule also implements section 802 of the act, which
applies to unapproved drug products intended for export. Section 802(c)
of the act applies to exports of unapproved drug products intended for
investigational use. As stated earlier, section 802(c) of the act
permits the export of a drug or device intended for investigational use
to Australia, Canada, Israel, Japan, New Zealand, Switzerland, South
Africa, or any country in the EU or EEA in accordance with the laws of
the importing country. No prior FDA authorization is required, and
exports under section 802(c) of the act are also exempt from regulation
under section 505(i) of the act. However, section 802(f) of the act
prohibits export of a drug if certain conditions are not met (such as
conformity with CGMPs, compliance with requirements contained in
section 801(e)(1) of the act, and not being adulterated under certain
provisions of section 501 of the act). Section 312.110(b)(3) pertains
to exports of investigational new drugs to listed countries, under
section 802(c) of the act. Additionally, Sec. 312.110(b)(2) pertains
to drugs exported under section 802(b) of the act and requires that
such exports comply with section 802(f) of the act.
Authority to issue regulations to implement section 802 of the act,
and for the efficient enforcement of the act generally, is contained in
section 701(a) of the act (21 U.S.C. 371(a)). Section 903 of the act
also provides general powers for implementing policies respecting FDA
programs and activities. Thus, the final rule implements sections
505(i) and 802 of the act. Furthermore, it is also authorized under our
rulemaking authorities at sections 505(i) and 701(a) of the act, and
FDA's general authority at section 903 of the act.
V. Environmental Impact
FDA has determined under 21 CFR 25.30(h) and (i), and 25.31(e) that
this action is of a type that does not individually or cumulatively
have a significant effect on the human environment. Therefore, neither
an environmental assessment nor an environmental impact statement is
required.
VI. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
VII. Paperwork Reduction Act of 1995
This final rule contains information collection provisions
requirements that are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). A description of these provisions is given below with an
estimate of the annual reporting and recordkeeping burden. Included in
the estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing each collection of information.
Title: Investigational New Drug Applications: Export Requirements
for Unapproved New Drug Products.
Description: The final rule provides four different mechanisms for
exporting an investigational new drug. First, an investigational new
drug may be exported under an IND to any country if the IND covers the
foreign clinical trial. Second, an investigational new drug that has
received valid marketing authorization from a listed country may be
exported for investigational use in any country subject to certain
conditions (such as being in substantial conformity with CGMPs). Third,
an investigational new drug may be exported to any listed country
without prior FDA authorization for use in a clinical investigation,
but would be subject to certain conditions (such as being in
substantial conformity with CGMPs). Fourth, an investigational new drug
may be exported provided that the sponsor submits a certification that
the drug meets certain export criteria at the time the drug is
exported. The final rule also requires persons exporting an
investigational new drug under either the second, third, or fourth
mechanisms to maintain records documenting their compliance with
statutory and regulatory requirements.
Description of Respondents: Businesses.
[[Page 70728]]
Table 1.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Recordkeepers per Recordkeeping Records Recordkeeper Total Hours
----------------------------------------------------------------------------------------------------------------
312.110(b)(2) 370 1 370 3 1,110
and (b)(3)
----------------------------------------------------------------------------------------------------------------
312.110(b)(4) 200 1 200 1 200
----------------------------------------------------------------------------------------------------------------
Total ................. .................... ................. ................. 1,310
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 2.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Respondents per Response Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
312.110(b)(4) 200 1 200 12 2,400
----------------------------------------------------------------------------------------------------------------
Total ................. ................. ................. ................. 2,400
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
The estimates are based on average export submissions in previous
years and on information supplied by industry sources. For the
recordkeeping requirement in Sec. 312.110(b)(2) and (b)(3), FDA used
the average annual number of export requests in previous years before
enactment of the FDA Export Reform and Enhancement Act (approximately
570) and subtracted the number of export requests that it currently
receives under the 312 program (200) to obtain an estimated 370
recordkeepers. These records, in general, would be subject to Sec.
1.101 (66 FR 65429), and the estimated burden hours for the relevant
parts of Sec. 1.101 total 3 hours. Thus, the total record burden hours
for Sec. 312.110(b)(2) and (b)(3) would be 1,110 hours (370 records
multiplied by 3 hours per record).
For Sec. 312.110(b)(4), industry sources indicated that most firms
already maintain records to demonstrate their compliance with export
requirements, so the agency assigned a value of 1 hour for each
response. The total recordkeeping burden for Sec. 312.110(b)(4),
therefore, is 200 hours (200 records multiplied by 1 hour per record).
Thus, the total recordkeeping burden would be 1,310 hours (1,110 +
200 = 1,310). Of this recordkeeping burden, 1,110 hours would be a
statutory burden (because section 802(g) of the act requires persons
exporting drugs under section 802 of the act to maintain records of
alldrugs exported and the countries to which they were exported).
For the reporting requirement in Sec. 312.110(b)(4), FDA's
experience under the 312 program suggests that extremely few reports
would be submitted. Assuming that 200 requests are received (the
current number of requests under the 312 program) and that the
reporting burden remains constant at approximately 12 hours per
response, the total burden under Sec. 312.110(b)(4) would be 2,400
hours. The reporting burden would be a regulatory (rather than
statutory) burden.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), the agency has submitted the information collection
provisions of this final rule to OMB for review. Prior to the effective
date of this final rule, FDA will publish a notice in the Federal
Register announcing OMB's decision to approve, modify, or disapprove
the information collection provisions in this final rule. An agency may
not conduct or sponsor, and a person is not required to respond to, a
collection of information unless it displays a currently valid OMB
control number.
VIII. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Under the Regulatory
Flexibility Act, unless an agency certifies that a rule will not have a
significant impact on small entities, the agency must analyze
regulatory options that would minimize the impact of the rule on small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $115 million, using the most current (2003) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
The agency has reviewed this final rule and determined that it is
consistent with the regulatory philosophy and the principles identified
in the Executive Order 12866 and these two statutes, as it will not
result in an expenditure of $100 million or more in any one year.
Because the rule raises novel policy issues, OMB has determined that
this final rule is a significant regulatory action as defined under
paragraph 4 of section 3(f) of Executive Order 12866.
The final rule facilitates exports of unapproved new drug products
for use in clinical investigations in foreign countries by eliminating
the need to submit requests for permission to export the drugs and to
receive FDA authorization. This change reduces the cost to the affected
small firms. Thus, the agency certifies that this final rule does not
have a significant economic impact on a substantial number of small
entities. Therefore, under the Regulatory Flexibility Act, no further
analysis is required.
Because the final rule does not impose any mandates on State,
local, or tribal governments, or the private sector
[[Page 70729]]
that will result in an expenditure of $100 million or more in any one
year, FDA is not required to perform a cost-benefit analysis under the
Unfunded Mandates Reform Act of 1995.
List of Subjects in 21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
312 is amended as follows:
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
0
1. The authority citation for 21 CFR part 312 is revised to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 371,
381, 382, 383, 393; 42 U.S.C. 262.
0
2. Section 312.110 is amended by revising paragraph (b) and by adding
paragraphs (c) and (d) to read as follows:
Sec. 312.110 Import and export requirements.
* * * * *
(b) Exports. An investigational new drug may be exported from the
United States for use in a clinical investigation under any of the
following conditions:
(1) An IND is in effect for the drug under Sec. 312.40, the drug
complies with the laws of the country to which it is being exported,
and each person who receives the drug is an investigator in a study
submitted to and allowed to proceed under the IND; or
(2) The drug has valid marketing authorization in Australia,
Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or in
any country in the European Union or the European Economic Area, and
complies with the laws of the country to which it is being exported,
section 802(b)(1)(A), (f), and (g) of the act, and Sec. 1.101 of this
chapter; or
(3) The drug is being exported to Australia, Canada, Israel, Japan,
New Zealand, Switzerland, South Africa, or to any country in the
European Union or the European Economic Area, and complies with the
laws of the country to which it is being exported, the applicable
provisions of section 802(c), (f), and (g) of the act, and Sec. 1.101
of this chapter. Drugs exported under this paragraph that are not the
subject of an IND are exempt from the label requirement in Sec.
312.6(a); or
(4) Except as provided in paragraph (b)(5) of this section, the
person exporting the drug sends a written certification to the Office
of International Programs (HFG-1), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, at the time the drug is first
exported and maintains records documenting compliance with this
paragraph. The certification shall describe the drug that is to be
exported (i.e., trade name (if any), generic name, and dosage form),
identify the country or countries to which the drug is to be exported,
and affirm that:
(i) The drug is intended for export;
(ii) The drug is intended for investigational use in a foreign
country;
(iii) The drug meets the foreign purchaser's or consignee's
specifications;
(iv) The drug is not in conflict with the importing country's laws;
(v) The outer shipping package is labeled to show that the package
is intended for export from the United States;
(vi) The drug is not sold or offered for sale in the United States;
(vii) The clinical investigation will be conducted in accordance
with Sec. 312.120;
(viii) The drug is manufactured, processed, packaged, and held in
substantial conformity with current good manufacturing practices;
(ix) The drug is not adulterated within the meaning of section
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;
(x) The drug does not present an imminent hazard to public health,
either in the United States, if the drug were to be reimported, or in
the foreign country; and
(xi) The drug is labeled in accordance with the foreign country's
laws.
(5) In the event of a national emergency in a foreign country,
where the national emergency necessitates exportation of an
investigational new drug, the requirements in paragraph (b)(4) of this
section apply as follows:
(i) Situations where the investigational new drug is to be
stockpiled in anticipation of a national emergency. There may be
instances where exportation of an investigational new drug is needed so
that the drug may be stockpiled and made available for use by the
importing country if and when a national emergency arises. In such
cases:
(A) A person may export an investigational new drug under paragraph
(b)(4) of this section without making an affirmation with respect to
any one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi),
(b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this section, provided
that he or she:
(1) Provides a written statement explaining why compliance with
each such paragraph is not feasible or is contrary to the best
interests of the individuals who may receive the investigational new
drug;
(2) Provides a written statement from an authorized official of the
importing country's government. The statement must attest that the
official agrees with the exporter's statement made under paragraph
(b)(5)(i)(A)(1) of this section; explain that the drug is to be
stockpiled solely for use of the importing country in a national
emergency; and describe the potential national emergency that warrants
exportation of the investigational new drug under this provision; and
(3) Provides a written statement showing that the Secretary of
Health and Human Services (the Secretary), or his or her designee,
agrees with the findings of the authorized official of the importing
country's government. Persons who wish to obtain a written statement
from the Secretary should direct their requests to Secretary's
Operations Center, Office of Emergency Operations and Security
Programs, Office of Public Health Emergency Preparedness, Office of the
Secretary, Department of Health and Human Services, 200 Independence
Ave. SW., Washington, DC 20201. Requests may be also be sent by FAX:
202-619-7870 or by e-mail: [email protected].
(B) Exportation may not proceed until FDA has authorized
exportation of the investigational new drug. FDA may deny authorization
if the statements provided under paragraphs (b)(5)(i)(A)(1) or
(b)(5)(i)(A)(2) of this section are inadequate or if exportation is
contrary to public health.
(ii) Situations where the investigational new drug is to be used
for a sudden and immediate national emergency. There may be instances
where exportation of an investigational new drug is needed so that the
drug may be used in a sudden and immediate national emergency that has
developed or is developing. In such cases:
(A) A person may export an investigational new drug under paragraph
(b)(4) of this section without making an affirmation with respect to
any one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v),
(b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi),
provided that he or she:
(1) Provides a written statement explaining why compliance with
each such paragraph is not feasible or is contrary to the best
interests of the individuals who are expected to receive the
investigational new drug and
(2) Provides sufficient information from an authorized official of
the importing country's government to enable the Secretary, or his or
her
[[Page 70730]]
designee, to decide whether a national emergency has developed or is
developing in the importing country, whether the investigational new
drug will be used solely for that national emergency, and whether
prompt exportation of the investigational new drug is necessary.
Persons who wish to obtain a determination from the Secretary should
direct their requests to Secretary's Operations Center, Office of
Emergency Operations and Security Programs, Office of Public Health
Emergency Preparedness, Office of the Secretary, Department of Health
and Human Services, 200 Independence Ave. SW., Washington, DC 20201.
Requests may be also be sent by FAX: 202-619-7870 or by e-mail:
[email protected].
(B) Exportation may proceed without prior FDA authorization.
(c) Limitations. Exportation under paragraph (b) of this section
may not occur if:
(1) For drugs exported under paragraph (b)(1) of this section, the
IND pertaining to the clinical investigation is no longer in effect;
(2) For drugs exported under paragraph (b)(2) of this section, the
requirements in section 802(b)(1), (f), or (g) of the act are no longer
met;
(3) For drugs exported under paragraph (b)(3) of this section, the
requirements in section 802(c), (f), or (g) of the act are no longer
met;
(4) For drugs exported under paragraph (b)(4) of this section, the
conditions underlying the certification or the statements submitted
under paragraph (b)(5) of this section are no longer met; or
(5) For any investigational new drugs under this section, the drug
no longer complies with the laws of the importing country.
(d) Insulin and antibiotics. New insulin and antibiotic drug
products may be exported for investigational use in accordance with
section 801(e)(1) of the act without complying with this section.
Dated: November 16, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-23120 Filed 11-22-05; 8:45 am]
BILLING CODE 4160-01-S